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标题翻译： 3“ - 异链霉素及其二氢衍生物，药物组合物及其制备方法

公开(公告)号：US4469683A

公开(公告)日：1984-09-04

申请号：US473921

申请日：1983-03-10

申请人： Hamao Umezawa , Sumio Umezawa , Tsutomu Tsuchiya , Tetsuo Shitara , Shuichi Sakamoto

发明人： Hamao Umezawa , Sumio Umezawa , Tsutomu Tsuchiya , Tetsuo Shitara , Shuichi Sakamoto

IPC分类号： A61K31/70 , A61K31/7028 , A61K31/7034 , A61K31/7036 , A61P31/04 , C07H15/238 , A61K31/71 , C07H15/22

CPC分类号： C07H15/238 , Y02P20/55

摘要： New semi-synthetic antibiotics, 3"-epistreptomycin and 3"-epidihydrostreptomycin are now provided, which are useful as antibacterial agents. 3"-Epidihydrostreptomycin is produced by a process comprising hydrolyzing an appropriately N,O-protected 2",3"-N,O-carbonyl-3"-epidihydrostreptomycin which is prepared by skilled introduction of amino-protecting groups and hydroxyl-protecting groups of appropriately selected natures into dihydrostreptomycin and intermolecular condensation of a particular pair of amino-protecting and hydroxyl-protecting groups so introduced. 3"-Epistreptomycin is produced by a process comprising oxidizing the 3'-hydroxymethyl group of an appropriately N,O-protected 3"-epidihydrostreptomycin as prepared by skilled introduction of amino-protecting groups and hydroxyl-protecting groups of appropriately selected natures, and then removing the remaining protective groups from the resultant N,O-protected 3"-epistreptomycin obtained as the oxidation product.SUMMARY OF THE INVENTIONThis invention relates to new streptomycin derivatives which are new substances and useful as antibacterial agents. More particularly, this invention relates to 3"-epistreptomycin and 3"-epidihydrostreptomycin and also to processes for the production of these new streptomycin derivatives.BACKGROUND OF THE INVENTIONStreptomycin is a well known antibiotic which was discovered by Wasksman. Streptomycin, and dihydrostreptomycin which is obtained by reduction of the aldehyde group of streptomycin are widely used as medicine in therapeutic treatment of bacterial infections. However, as streptomycin and dihydrostreptomycin become widely used, such strains of bacteria resistant to these antibiotics have occurred, and owing to this the therapeutic effects of streptomycin and dihydrostreptomycin have considerably been reduced. The occurrence of such resistant bacteria is generally observed not only with the antibiotics of streptomycin type but also with other antibiotics such as kanamycins, lividomycins and the like. These historical facts are detailed in the general remarks as reported by Hamao Umezawa who is one of the present inventors and is a first discoverer of the mechanism of resistance of bacteria against aminoglycosidic antibiotics (H. Umezawa; "Advances in Carbohydrate Chemistry and Biochemistry" Vol. 30, page 183, Academic Press 1974). With the streptomycins, it has been found that the hydroxyl group at 3"-position of the molecule of streptomycins can be adenylated by such resistant bacteria capable of producing streptomycin adenyl-transferase and thereby 3"-O-adenylstreptomycins are formed, with a consequence that streptomycins can be inactivated in respect of their antibacterial effects (Umezawa et al.; "Journal of Antibiotics" Vol. 21, page 81 (1968)). In these circumstances, we, the present inventors, have conducted studies in an attempt to remove the 3"-hydroxyl group from the streptomycin molecule and thereby to eliminate the possibility of inactivation of streptomycin which would occur due to the adenylation of the 3"-hydroxyl group of streptomycin, so that there was provided a new derivative of streptomycin which would be active also against the bacteria resistant to streptomycin. As a result of our study, we succeeded in synthesizing 3"-deoxydihydrostreptomycin from streptomycin, and we found that this 3"-deoxydihydrostreptomycin is active against the resistant bacteria (see Japanese patent application prepublication "Kokai" No. 105154/77; and "Journal of Antibiotics" Vol. 29, page 978 (1976)).We have made our further study and have now succeeded in effecting the epimerization of the 3"-hydroxyl group of streptomycin and dihydrostreptomycin, and we have now found that the 3"-epistreptomycin and 3"-epidihydrostreptomycin now newly synthetized are active against a variety of streptomycin-resistant bacteria. Thus, we have accomplished this invention.DETAILED DESCRIPTION OF THE INVENTIONAccording to a first embodiment of this invention, therefore, there are provided as new compounds a 3"-epistreptomycin compound represented by the general formula ##STR1## wherein R denotes a hydroxymethyl group--CH.sub.2 OH for 3"-epidihydrostreptomycin and R denotes an aldehyde group --CHO for 3"-epistreptomycin, and a pharmaceutically acceptable acid-addition salt thereof.The pharmaceutically acceptable acid-addition salt of the new compound of the above general formula (I) includes a salt of 3"-epistreptomycin or 3"-epidihydrostreptomycin with an ordinary, non-toxic acid such as an inorganic acid, for example, hydrochloric acid, sulfuric acid, phosphoric acid and the like, as well as an organic acid, for example, acetic acid, malonic acid, citric acid and the like.3"-Epistreptomycin tri-hydrochloride mono-hydrate according to this invention is in the form of a colorless, solid substrance which shows a specific optical rotation [.alpha.].sub.D.sup.23 -80.degree. (c 1, water) but shows no definite melting point. Its elemental analysis (Found: C 35.22, H 6.51, N 13.58%) was coincident with the theoretical value of the empirical formula C.sub.21 H.sub.39 N.sub.7 O.sub.12. 3HCl.H.sub.2 O (Calculated: C 35.58, H 6.26, N 13.83%).3"-Epidihydrostreptomycin 3/2 carbonate according to this invention is in the form of a colorless, solid substance which shows a specific optical rotation [.alpha.].sub.D.sup.23 -79.degree. (c 0.9, water) but shows no definite melting point. Its elemental analysis (Found: C 39.63, H 6.47, N 14.33%) was coincident with the theoretical value of the empirical formula (C.sub.21 H.sub.41 N.sub.7 O.sub.12.3/2H.sub.2 CO.sub.3) (Calculated: C 39.94, H 6.55, N 14.49%).The antibacterial activities of 3"-epistreptomycin and 3"-epidihydrostreptomycin are demonstrated in Table 1 below, which exhibits the minimum inhibitory concentrations (mcg/ml) of the new compounds of this invention as estimated according to a standard serial dilution method using a nutrient agar medium as the incubation medium, the incubation being made at 37.degree. C. for 17 hours. Minimum inhibitory concentrations (mcg/ml) of streptomycin and dihydrostreptomycin were also estimated in the same manner as above for the comparison purpose and are shown in Table 1 below. As shown in Table 1, the new compounds of the formula (I) according to this invention exhibit antibacterial spectra similar to those of the comparative dihydrostreptomycin and show remarkably improved antibacterial activities against gram-negative bacteria, especially against various resistant strains of Escherichia coli. TABLE 1 __________________________________________________________________________ MIC (mcg/ml) Dihydro- 3"-Epidihydro- 3"-Epi- streptomycin Streptomycin Test organism streptomycin streptomycin (comparative) (comparative) __________________________________________________________________________Staphylococcus aureus 209P 3.12 3.12 3.12 3.12 Staphylococcus aureus AP01 3.12 3.12 1.56 3.12 Sarcia lutea PCI 1001 1.56 3.12 1.56 1.56 Bacillus subtilis NRRL B558 3.12 1.56 3.12 0.78 Salmonella typhi T-63 0.78 1.56 25 25 Escherichia coli K-12 1.56 1.56 1.56 1.56 Escherichia coli K-12 R5 6.25 6.25 >100 >100 Escherichia coli K-12 ML1629 1.56 3.12 100 >100 Escherichia coli K-12 ML1630 3.12 3.12 >100 >100 Escherichia coli K-12 ML1630 25 25 >100 >100 R8125 Escherichia coli W677 1.56 1.56 0.78 1.56 Escherichia coli JR66/W677 12.5 12.5 >100 >100 Escherichia coli C600 R135 3.12 3.12 50 50 Providencia sp. pv16 6.25 3.12 25 25 Pseudomonas aeruginosa 33 3.12 6.25 1.56 3.12 Pseudomonas aeruginosa No. 12 25 25 25 25 Pseudomonas aeruginosa 13--13 50 50 >100 >100 Mycobacterium smegmatis 607 0.78 1.56 0.78 0.78 __________________________________________________________________________The new compounds of this invention, namely 3"-epistreptomycin and 3"-epidihydrostreptomycin can be administered to living animals, including men, safely as much as the known streptomycin and dihydrostreptomycin for therapeutical treatment of bacterial infections, because they are of low toxicity as will be shown by the fact that when acute toxicity of 3"-epistreptomycin or 3"-epidihydrostreptomycin was estimated by intravenous injection of these compounds in groups of mice (ICR mice, adult, female, body weight 20 g..+-.0.5 g. six in each group), all the treated mice survived for more than 14 days after the new compound of this invention was administered intravenously into each mouse at a dosage of 4 mg/kg (LD.sub.50 more than 200 mg/kg).Processes for the production of the new compounds of the formula (I) according to this invention are described in the following.Briefly, 3"-epidihydrostreptomycin of this invention is produced starting from the known dihydrostreptomycin, and 3"-epistreptomycin of this invention is produced form the 3"-epidihydrostreptomycin now newly synthetized.Firstly, a summary of a process for the production of 3"-epidihydrostreptomycin is illustrated by the following first flow diagram which shows the production of 3"-epidihydrostreptomycin from dihydrostreptomycin via about eight stages. In the first flow diagram and also in the another flow diagrams shown later, such intermolecular sites of the compound which just have undergone chemical change or modification through the chemical reaction at a particular stage of the concerned process are preferentially represented in the respective flow diagrams, so that such substituent or substituents which is or are existing in the compound in one particular stage but is or are remaining unchanged in the compound in the next stage (that is, the stage just following said particular stage) are sometimes omitted from being shown in the next stage of the flow diagram, for sake of simplicity. In the following flow diagrams, Ac denotes an acetyl group. ##STR2##Now, a process of producing 3"-epidihydrostreptomycin is described with reference to the respective stages of the process shown in the first flow diagram as above and is fully illustrated by Example 1 given later.Dihydrostreptomycin which is used as the starting substance in this process is the compound represented by the formula (1) in the first flow diagram. To synthetize 3"-epidihydrostreptomycin of this invention with starting from dihydrostreptomycin, at first, the 2"-methylamino group of the compound of the formula (1) is selectively protected in Stage A of the process by a known aminoprotecting group such as an aralkyloxycarbonyl group, preferably benzyloxycarbonyl group. To this end, the starting compound of the formula (1) may preferably be reacted with a 1 molar or substantially 1 molar proportion of benzyloxycarbonyl chloride in a mixture of water and acetone at a temperature of -20.degree. C. to 50.degree. C., preferably at 0.degree. C. under ice-cooling in the presence of a base, preferably an alkali metal carbonate such as sodium carbonate, whereby the preferential benzyloxycarbonylation of the 2"-methylamino group takes place to produce 2"-N-benzyloxycarbonyldihydrostreptomycin briefly represented by the formula (2) in the first flow diagram.Then, in Stage B of this process, a pair of two 3'- and 3'a-hydroxyl groups as well as a pair of two 4"- and 6"-hydroxyl groups of the compound of the formula (2) are protected by a known di-valent hydroxyl-protecting group such as an alkylidene group, preferably isopropylidene group. For this purpose, the compound of the formula (2) may preferably be reacted with 2,2-dimethoxypropane in anhydrous dimethylformamide (DMF) in the presence of a reaction catalyst such as p-toluenesulfonic acid, whereby the pair of the two 3'- and 3'a-hydroxyl groups as well as the pair of the two 4"- and 6"-hydroxyl groups of the compound of the formula (2) are each protected simultaneously by a single isopropylidene group, to afford 2"-N-benzyloxycarbonyl-3',3'a; 4", 6"-di-O-isopropylidene-dihydrostreptomycin briefly represented by the formula (3) in the first flow diagram.Thereafter, in Stage C of this process, all the remaining free (four) hydroxyl groups and all the two guanidyl groups of the compound of the formula (3) are protected, respectively. To this end, all these functional hydroxyl and guanidyl groups may preferably be blocked by acetyl groups. The acetylation reagent available for this purpose may be acetic anhydride as used in the presence of sodium acetate. Thus, the compound of the formula (3) is reacted with acetic anhydride in the presence of sodium acetate using an excess of acetic anhydride as the reaction medium, when there is produced tetra-N-.sup.G -acetyl-2,5,6,3"-tetra-O-acetyl-2"-N-benzyloxycarbonyl-3',3'a; 4", 6"-di-O-isopropylidene-dihydrostreptomycin represented by the formula (4) in the first flow diagram.Further, in Stage D of this process, the compound of the formula (4) is treated so as to remove preferentially the 2"-N-benzyloxycarbonyl group therefrom and thereby liberate the free 2"-methylamino group. For this purpose, the compound of the formula (4) may preferably be subjected to catalytic hydrogenolysis with hydrogen in the presence of a known hydrogenolysis catalyst such as palladium black as be conducted conventionally in the deprotection technique for removal of the amino-protecting benzyloxycarbonyl group. There is thus formed tetra-N.sup.G -acetyl-2,5,6,3"-tetra-O-acetyl-3',3'a; 4",6"-di-O-isopropylidene-dihydrostreptomycin briefly represented by the formula (5) in the first flow diagram.Moreover, in Stage E of the present process, the compound of the formula (5) is treated so as to remove preferentially the blocking acetyl group from the 3"-hydroxyl group of the compound (5). For this purpose, the compound (5) is dissolved in a volume of ethanol, and the resulting ethanolic solution is allowed to stand at a temperature of 20.degree.-30.degree. C. for 1 day or usually for a period of about 3 days, whereby the selective removal of the 3"-O-acetyl group takes place through the ethanolysis. This unique fact that the blocking acetyl group can be removed only from the 3"-hydroxyl group of the compound (5) while the other blocking O-acetyl groups are not cleaved out of the 2-, 5- and 6-hydroxyl groups of said compound is unexpected and surprising. Through this Stage E, there is formed tetra-N.sup.G -acetyl-2,5,6-tri-O-acetyl-3',3'a; 4",6"-di-O-isopropylidenedihydrostreptomycin briefly represented by the formula (6) in the first flow diagram.Then, in Stage F of the present process, the 2"-methylamino group of the compound of the formula (6) is again protected by a benzyloxycarbonyl group. To this end, the compound of the formula (6) may either be reacted with benzyloxycarbonyl chloride in the same manner as in the aforesaid Stage A, or may be reacted with benzyloxycarbonyl chloride in chloroform in the presence of sodium hydrogen carbonate. In this way, there is produced tetra-N.sup.G -acetyl-2,5,6-tri-O-acetyl-2"-N-benzyloxycarbonyl-3',3'a; 4",6"-di-O-isopropylidenedihydrostreptomycin birefly represented by the formula (7) in the first flow diagram.Thereafter, in Stage G of the present process, the compound of the formula (7) is dissolved into a volume of a suitable organic solvent such as dichloromethane and the resultant solution of the compound (7) is reacted with a 1-10 molar proportion of trifluoromethanesulfonic acid anhydride in the presence of pyridine under cooling (preferably at a temperature of approximately -50.degree. C..about.+50.degree. C.), so that there is once formed an unstable 3"-O-trifluoromethylsulfonyl derivative of the compound (7) as a glassy material. This glassy material is then dissolved into a volume of pyridine and allowed to stand at a temperature of 10.degree. C..about.100.degree. C., preferably at ambient temperature, when the 3"-trifluoromethylsulfonyl group is interacted and condensed with the 2"-benzyloxycarbonylmethylamino group, so that the cyclisation reaction takes place to form a cyclic carbamate group, giving the compound of the formula (8) briefly shown in the first flow diagram, namely tetra-N.sup.G -acetyl-2,5,6-tri-O-acetyl-2",3"-N,O-carbonyl-3"-epi-3',3'a; 4",6"-di-O-isopropylidenedihydrostreptomycin.Finally, in Stage H of the present process, the compound of the formula (8) is subjected to an N,O-deprotecting treatments as well as removal of the 2",3"-N,O-carbonyl group by a hydrolytic ring-fission thereof. That is, the removal of the N,O-protecting acetyl groups and the removal of the cyclic carbamate group (the 2",3"-N,O-carbonyl group) from the compound of the formula (8) are effected in this Stage H. For this purpose, the compound of the formula (8) may conveniently by hydrolyzed in aqueous tetrahydrofuran in the presence of barium hydroxide, so that both of the acetyl groups and the cyclic carbamate group can be removed at once. The liberated 3"-hydroxyl group which has undergone the decarbonylation just at this stage of removal of the 2",3"-N,O-carbonyl group is remaining inversed in the epi-position, so that there is formed 3"-epi-3',3'a; 4",6'-di-O-isopropylidenedihydrostreptomycin. The latter compound is further necessary in this Stage H to be subjected to removal of the 3',3'a; 4",6"-di-O-isopropylidene groups therefrom, and this can be achieved according to a conventional method for removing the isopropylidene group known in the usual deprotection technique. For instance, the removal of the 3',3'a; 4",6"-di-O-isopropylidene groups may be accomplished by hydrolyzing the intermediate 3"-epi-3',3'a; 4",6"-di-O-isopropylidenedihydrostreptomycin in aqueous acetic acid. In this way, there is produced the aimed 3"-epidihydrostreptomycin, represented by the formula (I') in the first flow diagram.In the foregoing descriptions, the process of producing the compound of the formula (I') of this invention is described with reference to such a case where the benzyloxycarbonyl group, isopropylidene group and acetyl group are particularly selected as the protective groups. It will be self-evident, however, that the required, N,O-protection of the concerned compounds can be achieved using such a known amino-protecting group which serves equivalently to the benzyloxycarbonyl group; and such a known guanidyl-amino (or imino) protecting group which serves equivalently to the acetyl group, as well as such known hydroxyl-protecting groups which serve equivalently to the isopropylidene group and acetyl group, respectively.According to a second embodiment of this invention, therefore, there is provided a process for the production of 3"-epidihydrostreptomycin, which comprises the consecutive steps of:(a) Reacting tetra-N.sup.G -acetyl-2,5,6,3"-tetra-O-acetyl-3',3'a; 4", 6"-di-O-isopropylidene-dihydrostreptomycin of the formula ##STR3## wherein Ac denotes an acetyl group, with ethanol at a temperature of 20.degree.-30.degree. C. to effect preferential removal of the 3"-O-acetyl group from the above N,O-protected dihydrostreptomycin compound and thereby to produce tetra-N.sup.G -acetyl-2,5,6-tri-O-acetyl-3',3'a; 4", 6"-O-isopropylidenedihydrostreptomycin,(b) Reacting the product of the step (a) just above with benzyloxycarbonyl chloride to produce tetra-N.sup.G -acetyl-2,5,6-tri-O-acetyl-2"-N-benzyloxycarbonyl-3',3'a; 4",6"-di-O-isopropylidene-dihydrostreptomycin,(c) Reacting the product of the step (b) just above with trifluoromethanesulfonic acid anhydride in pyridine at a temperature of -50.degree. C. to 50.degree. C. to form the 30"-O-trifluoromethylsulfonyl derivative thereof, followed by allowing the latter derivative to stand in solution in pyridine at a temperature of 10.degree. C. to 100.degree. C. to produce tetra-N.sup.G -acetyl-2,5,6-tri-O-acetyl-2",3"-N,O-carbonyl-3"-epi-3',3'a; 4",6"-di-O-isopropylidene-dihydrostreptomycin of the formula ##STR4## wherein Ac is as defined as above.(d) Hydrolyzing the product of the step (c) just above with water in the presence of barium hydroxide to remove all the acetyl groups and the 2",3"-N,O-carbonyl group therefrom and thus to produce 3"-epi-3',3'a; 4",6"-di-O-isopropylidene-dihydrostreptomycin, and(e) Hydrolyzing the product of the step (d) just above to remove the 3',3'a; 4",6"-di-O-isopropylidene groups therefrom and thus to produce the desired 3"-epidihydrostreptomycin.Besides, the second new compound of this invention, namely 3"-epistreptomycin can be produced with starting from the 3"-epidihydrostreptomycin now newly synthetized as above. A summary of such a process of producing 3"-epistreptomycin is illustrated by the following second flow diagram, where such intermolecular sites of the compound which just have undergone chemical change or modification through the chemical reaction at one particular stage of the process concerned are preferentially represented, so that such substituent or substituents which is or are existing in the concerned compound in one particular stage but is or are remaining unchanged in the next stage following said particular stage are sometimes omitted from being shown in the next stage of the second flow diagram, for sake of simplicity. ##STR5##In the following, a process of producing 3"-epistreptomycin from 3"-epidihydrostreptomycin is described with reference to the respective stages of the process shown in the second flow diagram as above and is fully illustrated by Example 2 given later.3"-Epidihydrostreptomycin which is employed as the starting substance in this process is the compound of the formula (I') shown in the first flow diagram given hereinbefore. In Stage I of this process, the 2"-methylamino group of the starting compound of the formula (I') is at first protected preferentially with benzyloxycarbonyl group by reacting the starting compound (I') with benzyloxycarbonyl chloride in the same manner as in Stage A of the process according to the first flow diagram. There is thus formed 2"-N-benzyloxycarbonyl-3"-epidihydrostreptomycin of the formula (9) shown in the second flow diagram, which is usually obtained in the form of its hydrochloride.In Stage J of this process, a pair of two 3'- and 3'a-hydroxyl groups of the compound of the formula (9) is protected with a known di-valent hydroxyl-protecting group such as an alkylidene group. To this end, the compound of the formula (9) may be reacted with an excess over the 1 molar proportion of 2,2-dimethoxypropane in anhydrous DMF in the presence of p-toluenesulfonic acid, so that the desired mono-O-isopropylidenated product is formed in mixture with some poly-O-isopropylidenated products. The poly-O-isopropylidenated products can be converted into the desired mono-O-isopropylidenated product by treatment with aqueous acetic acid. There is thus produced 2"-N-benzyloxycarbonyl-3"-epi-3',3'a-O-isopropylidenedihydrostreptomycin of the formula (10) briefly shown in the second flow diagram.In the next stage K of this process, all the remaining free hydroxyl groups and all the guanidyl groups of the compound of the formula (10) are protected with suitable protective groups. For this purpose, the compound of the formula (10) may preferably be acetylated in the same manner as in Stage C of the process according to the first flow diagram, that is, by reacting with a 10 molar proportion or more of acetic anhydride in the presence of sodium acetate. By this Stage K, there is produced tetra-N.sup.G -acetyl-2,5,6,3",4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-epi-3',3'a-O-isopropylidenedihydrostreptomycin of the formula (11) briefly shown in the second flow diagram.In Stage L of this process, the compound of the formula (11) is then subjected to removal of the 3',3'a-O-isopropylidene group therefrom in the same manner as in Stage H of the process according to the first flow diagram, by hydrolyzing the compound (11) in aqueous acetic acid, so that there is produced the compound of the formula (12) briefly shown in the second flow diagram, namely tetra-N.sup.G -acetyl-2,5,6,3",4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-epidihydrostreptomycin.Next, in Stage M of the present process, the 3'-hydroxymethyl group (the methylol group) of the compound of the formula (12) is oxidized into the aldehyde group --CHO. To this end, the compound of the formula (12) may preferably be reacted with dimethylsulfoxide as an oxidation reagent in the presence of pyridine, trifluoroacetic acid and dicyclohexylcarbodiimide. There is thus produced tetra-N.sup.G -acetyl-2,5,6,3",4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-epistreptomycin (which is not shown in the second flow diagram). The latter aldehyde compound is then subjected to removal of the acetyl groups therefrom, and this deacetylation may conveniently be effected by hydrolysing said aldehyde compound with concentrated aqueous ammonia in methanol. In this way, there is produced 2"-N-benzyloxycarbonyl-3"-epistreptomycin of the formula (13) shown in the second diagram.After the above deacetylation step, in the final Stage N of the present process, the compound of the formula (13) is subjected to removal of the 2"-N-benzyloxycarbonyl group therefrom to give the desired 3"-epistreptomycin of the formula (I") shown in the second diagram. To remove the 2"-N-benzyloxycarbonyl group from the compound (13), the latter compound may conveniently be subjected to a conventional catalytic hydrogenolysis with hydrogen in the presence of a known hydrogenolysis catalyst such as palladium black according to the known deprotection technique.According to a third embodiment of this invention, therefore, there is provided a process for the production of 3"-epistreptomycin which comprises the consecutive steps of:(a) Reacting 3"-epidihydrostreptomycin with a 1 molar or substantially 1 molar proportion of benzyloxycarbonyl chloride in a mixture of water and acetone at a temperature of -20.degree. C. to 50.degree. C. in the presence of an alkali metal carbonate to selectively benzyloxycarbonylate the 2"-methylamino group of 3"-epidihydrostreptomycin and thereby to produce 2"-N-benzyloxycarbonyl-3"-epidihydrostreptomycin,(b) Reacting the product of the step (a) just above with 2,2-dimethoxypropane in the presence of p-toluenesulfonic acid to produce 2"-N-benzyloxycarbonyl-3"-epi-3',3'a-O-isopropylidene-dihydrostreptomycin,(c) Reacting the product of the step (b) just above with acetic anhydride in the presence of sodium acetate to produce tetra-N.sup.G -acetyl-2,5,6,3",4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-epi-3,3'a-O-isopropylidene-dihydrostreptomycin,(d) Hydrolyzing the product of the step (c) just above with aqueous acetic acid to produce tetra-N.sup.G -acetyl-2,5,6,3",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-epidihydrostreptomycin,(e) Oxidizing the 3'-hydroxymethyl group of the product of the step (d) just above by reacting the latter compound with dimethylsulfoxide in the presence of pyridine, trifluoroacetic acid and dicyclohexylcarbodiimide to produce tetra-N.sup.G -acetyl-2,5,6,3",4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-epistreptomycin,(f) Removing all the acetyl groups from the product of the step (e) just above by hydrolysis to produce 2"-N-benzyloxycarbonyl-3"-epistreptomycin, and(g) Subjecting the 2"-N-benzyloxycarbonyl-3"-epistreptomycin to a catalytic hydrogenolysis to remove the 2"-N-benzyloxycarbonyl group therefrom and thus to produce the desired 3"-epistreptomycin.We have further found it also possible to produce 3"-epidihydrostreptomycin of the formula (I') through a route different from the route of the process according to the first flow diagram, via the 2"-N-benzyloxycarbonyl-dihydrostreptomycin of the formula (2) obtained as an intermediate product. Thus, a further process of producing 3"-epidihydrostreptomycin via the intermediate compound of the formula (2) is briefly shown in the following third flow diagram and is fully illustrated by Example 3 given later. The third flow diagram is shown in brief similarly to the first and second flow diagrams in such way that the intermolecular sites of the compound which just have undergone chemical change or modification at one particular reaction stage are preferentially shown while such sites of the compound which are remaining unchanged at that particular reaction stage are not shown in the third flow diagram. ##STR6##In the process according to the third flow diagram as above, Stage O of this process is to effect the protective N,O-acetylation of the 2"-N-benzyloxycarbonyl-dihydrostreptomycin, namely the compound of the formula (2) shown in the first flow diagram and may be conducted in a similar manner to Stage C of the process according to the first flow diagram or to Stage K of the process according to the second flow diagram. In Stage O of this process, therefore, the compound of the formula (2) may preferably be reacted with a 11 molar proportion or more of acetic anhydride in the presence of sodium acetate using an excess of the acetic anhydride as the reaction medium to acetylate all the remaining free hydroxyl groups (seven) (excepting the 3'-hydroxyl group) and all the two guanidyl groups of the compound of the formula (2) and thereby to produce tetra-N.sup.G -acetyl-2,5,6,3'a,3",4",6"-hepta-O-acetyl-2"-N-benzyloxycarbonyldihydrostreptomycin represented by the formula (14) in the third flow diagram.Step P of this process is to de-benzyloxycarbonylate the compound of the formula (14) and may be carried out in the same manner as in Stage D of the process according to the first flow diagram. Thus, the compound of the formula (14) may be subjected to a conventional catalytic hydrogenolysis with hydrogen in the presence of a known hydrogenolysis catalyst such as palladium black to remove the 2"-N-benzyloxycarbonyl group from said compound and thereby to produce tetra-N.sup.G -acetyl-2,5,6,3'a,3",4",6"-hepta-O-acetyl-dihydrostreptomycin briefly represented by the formula (15) in the third flow diagram.Stage Q of this process is to effect a preferential removal of the 3"-O-acetyl group from the compound of the formula (15) and may be carried out in the same manner as in Stage E of the process according to the first flow diagram. Thus, the compound of the formula (15) is dissolved in a volume of ethanol and the resultant ethanolic solution is allowed to stand at a temperature of 20.degree.-30.degree. C. for 1 day or more, whereby the preferential removal of the 3"-O-acetyl gropu from the 3"-hydroxyl group of the compound (15) takes place through ethanolysis. This fact that the blocking acetyl group can be removed only from the 3"-hydroxyl group of the compound (15) while all the other blocking O-acetyl groups are not cleaved out of the compound (15) is unexpectable and surprising. Through this Stage Q, there is produced tetra-N.sup.G -acetyl-2,5,6,3'a,4",6"-hexa-O-acetyl-dihydrostreptomycin briefly represented by the formula (16) in the third flow diagram.Stage R of this process is to effect re-introduction of benzyloxycarbonyl group into the 2"-methylamino group of the compound of the formula (16) and may be conducted in the same manner as in Stage F of the process according to the first flow diagram. Thus, the compound of the formula (16) may either be reacted with benzyloxycarbonyl chloride in a mixture of water and acetone under icecooling in the presence of an alkali metal carbonate or may be reacted with benzyloxycarbonyl chloride in chloroform in the presence of sodium hydrogen carbonate. By this Stage R, there is produced tetra-N.sup.G -acetyl-2,5,6,3'a,4"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-dihydrostreptomycin briefly represented by the formula (17) in the third flow diagram.Stage S of this process is to methanesulfonylate the 3"-hydroxyl group of the compound of the formula (17) and may be conducted by reacting the compound (17) with a 1 molar or substantially 1 molar proportion of methanesulfonyl chloride in pyridine at a temperature of -50.degree. C. to +50.degree. C. By this Stage S, there is produced tetra-N.sup.G -acetyl-2,5,6,3'a,4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-O-methylsulfonyl-dihydrostreptomycin briefly represented by the formula (18) in the third flow diagram.Stage T of the present process is to convert the compound of the formula (18) into a 2",3"-N,O-carbonylated derivative thereof. For this purpose, the compound of the formula (18) may be dissolved in a volume of 2-methoxy-ethanol and the resultant solution is heated to an elevated temperature of 50.degree. C. to 100.degree. C. in the presence of sodium acetate, or alternatively the compound of the formula (18) may be reacted with sodium methylate in methanol at a temperature of -20.degree. C..about.+50.degree. C., preferably at ambient temperature, whereby the 3"-methylsulfonyloxy group is interacted and condensed with the 2"-benzyloxycarbonyl-(methyl)amino group, so that the cyclisation reaction occurs to form the 2",3"-N,O-carbonyl group (the cyclic 2",3"-N,O-carbamate group), with concomitantly involving the reaction for removal of all the acetyl groups. In this way, there is produced 2",3"-N,O-carbonyl-3"-epidihydrostreptomycin of the formula (19) shown in the third flow diagram (see Example 3(f), (g) given later).Stage U of the present process is to effect the hydrolytic ring-fission of the cyclic cis-2",3"-N,O-carbamate group of the compound of the formula (19). Thus, this Stage U may be accomplished by hydrolyzing the compound of the formula (19) with water in the presence of barium hydroxide in tetrahydrofuran, whereby the 2",3"-N,O-carbonyl group (the cyclic 2",3"-N,O-carbamate group) can be removed by the ring-fission thereof from the compound of the formula (19) and the 3"-hydroxyl group so liberated is remaining inversed in the epi-position, to afford the desired 3"-epidihydrostreptomycin, namely the compound of the formula (I') in the third flow diagram.According to a fourth embodiment of this invention, therefore, there is provided a process for the production of 3"-epidihydrostreptomycin, which comprises the consecutive steps of:(a) Reacting tetra-N.sup.G -acetyl-2,5,6,3'a, 3",4",6"-hepta-O-acetyl-dihydrostreptomycin of the formula ##STR7## wherein Ac denotes an acetyl group, with ethanol at a temperature of 20.degree.-30.degree. C. to effect preferential removal of the 3"-O-acetyl group from the above-mentioned N,O-acetylated dihydrostreptomycin compound and thereby to produce tetra-N.sup.G -acetyl-2,5,6,3'a,4",6"-hexa-O-acetyldihydrostreptomycin,(b) Reacting the product of the step (a) just above with benzyloxycarbonyl chloride to produce tetra-N.sup.G -acetyl-2,5,6,3'a,4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyldihydrostreptomycin,(c) Reacting the product of the step (b) just above with methanesulfonyl chloride in pyridine to produce tetra-N.sup.G -acetyl-2,5,6,3'a,4",6"-hexa-O-acetyl-2"-N-benzyloxycarbonyl-3"-O-methylsulfonyl-dihydrostreptomycin,(d) Reacting the product of the step (c) just above either with 2-methoxyethanol at a temperature of 50.degree. C. to 100.degree. C. or with sodium methylate in methanol at a temperature of -20.degree. C..about.50.degree. C., to produce 2",3"-N,O-carbonyl-3"-epi-dihydrostreptomycin, and(e) Hydrolyzing the product of the step (d) just above with water in the presence of barium hydroxide to remove the 2",3"-N,O-carbonyl group therefrom and thus to produce the desired 3"-epidihydrostreptomycin.As stated hereinbefore, the new compounds of this invention, namely 3"-epistreptomycin and 3"-epidihydrostreptomycin are of a low toxicity. The new compounds of this invention are each effective in therapeutic treatment of bacterial infections when administered intramuscularly in a dosage of from about 100 mg to about 1000 mg per day in divided dosages three or four times a day. Generally, the new compounds of this invention may be administered orally, intraperitoneally, intravenously or intramuscularly using any pharmaceutical form known in the art for such administration and in a similar manner to streptomycin and dihydrostreptomycin. Examples of pharmaceutical forms for oral administration are powders, capsules, tablets, syrup and the like. The new compounds of this invention may also be formulated into an aqueous injectable solution.According to a fifth embodiment of this invention, therefore, there is provided an antibacterial composition comprising an antibacterially effective amount of 3"-epistreptomycin or 3"-epidihydrostreptomycin as the active ingredient, in combination with a pharmaceutically acceptable carrier for the active ingredient.This invention is now illustrated with reference to the following Examples which show the production of the new compounds of this invention.

摘要翻译：现在提供新的半合成抗生素，3“ - 上链霉素和3” - 表型氢化链霉素，它们可用作抗菌剂。 3“ - 表型二氢链霉素通过包括水解适当的N，O-保护的2'，3” - N，O-羰基-3“ - 表达氢链霉素的方法产生，其通过熟练地引入氨基保护基团而制备，适当选择性质的羟基保护基团转化为二氢链霉素，并引入特定的一对氨基保护基和羟基保护基团的分子间缩合。 3“ - 异链霉素通过包括氧化适当的N，O-保护的3” - 表型氢化链霉素的3'-羟甲基的方法产生，其通过熟练地引入氨基保护基团和适当选择的性质的羟基保护基团，然后从作为氧化产物获得的所得N，O-保护的3“ - 表链霉素中除去剩余的保护基团。

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